Obesity-Associated Colorectal Cancer

Abstract

Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies.

Keywords: colorectal cancer; epidemiology; molecular factors; obesity; risk factors; targets; treatments.

Figure 1

The epidemiology of colorectal cancer (CRC) associated with obesity. Obesity is associated with an increased risk of developing CRC. A positive correlation has been identified between body mass index and the presence of adenomatous polyps, which may develop into CRC. It has been demonstrated that visceral adiposity is associated with colorectal adenoma (CRA), the precursor of CRC. CRC can be sporadic or hereditary. Lynch syndrome is a form of hereditary cancer. Obesity increases the risk of CRC in patients with Lynch syndrome.

Figure 2

Risk factors contributing to the development of obesity-associated colorectal cancer (CRC). Obesity, diet, and comorbidities play a crucial role in the development of CRC. MASLD, metabolic dysfunction-associated steatotic liver disease; PUFA, polyunsaturated fatty acids; SFA, long-chain saturated fatty acids; VAT, visceral adipose tissue; ↑, high; ↓, low.

Figure 3

Molecular and cellular factors that are key players involved in the relationship between obesity and colorectal cancer (CRC) development. (A) Relationship of visceral adipose tissue (VAT) to systemic inflammation as a driver of CRC development. VAT leads to the production of adipokines; accumulation of innate immune cells, such as M1-polarized macrophages secreting IL-1β, IL-6, and TNF-α, and IL-23-secreting macrophages and dendritic cells; T-cell infiltration, such as CD4+ Th1 T cells secreting TNF-α and IFN-γ and CD8+ T cells; B-cell infiltration secreting IL-6 and IFN-γ; and lipid peroxidation leading to 4-HNE and MDA production, causing DNA damage, metabolic reprogramming, and apoptosis. All these events induce systemic inflammation that favors CRC development. (B) Characteristics of obesity-related events associated with CRC risk. Obesity-related events such as moderate or severe obesity, metabolic syndrome, MASLD, and weight gain lead to an increased risk of CRC through various mechanisms, such as hyperleptinemia, insulin resistance, hypertension, atherogenic dyslipidemia, hepatic adiposopathy, or increased basal Glc in fasting blood. 4-HNE: 4-hydroxy-2-nonenal; Glc: glucose; IGF-1: insulin-like growth factor 1; IL: interleukin; IFN-γ: interferon γ; MASLD: metabolic dysfunction-associated steatotic liver disease; MDA: malondialdehyde; TNF-α: tumor necrotic factor α; VAT: visceral adipose tissue; ↑, elevated.

Figure 4

Obesity-associated colorectal cancer (CRC) molecular factors associated with cancer hallmarks. Schematic representation of major molecular targets involved in CRC related to obesity. APC: adenomatous polyposis coli; ARHGEF4: rho guanine nucleotide exchange factor 4; CIMP: CpG island methylation phenotype; CXCL12: C-X-C motif chemokine 12; CXCR4: C-X-C chemokine receptor type 4; EMT: epithelial–mesenchymal transition; EPHB2: EPH receptor B2; IL-6: interleukin 6; KRAS: Kirsten rat sarcoma virus; MACROD2: mono-ADP ribosylhydrolase 2; MTOR: mammalian target of rapamycin; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; SCFA: short-chain fatty acid; SCL2A1: solute carrier family 2 member 1; SOCS3: suppressor of cytokine signaling 3; TAMs: tumor-associated macrophages; TANs: tumor-associated neutrophils; TNFα: tumor necrosis factor α; TP53: tumoral protein 53; Tregs: regulatory T cells; ZSCAN30: zinc finger and SCAN domain containing 30; ZNF543: zinc finger protein 543; ↑, high; ↓, low.